1. Field of the Invention
This invention relates to an artificial organ and, more particularly to a liver bioreactor for hepatocyte culturing and use thereof.
2. Related Art
If an effective hepatic assist system existed, it could serve as a bridge to transplantation. Most of the patients waiting for a liver transplantation have chronic liver insufficiency but are not in hepatic coma shock. Various hepatic-assist systems have been used to salvage patients with acute liver insufficiency. Most attempts have been disappointing.
During the past decade, methodologies involving the use of membrane plasma separation techniques have been introduced into the field of hepatic support. Conventional methods, such as hemoperfusion hemofiltration, and dialysis have been improved. However, the application of the most up to date hepatic assist techniques has not improved the survival rate of patients with acute hepatic failure. For the most part, this may be attributed to our limited understanding of the pathology of hepatic failure.
On the other hand, with improvements in immunology and surgical techniques, liver transplantation has become an established therapeutic modality for the fatal liver diseases. It must still be recognized, however, that the regenerative capacity of the liver is almost unlimited. Whether the hepatic injury be viral, toxic, or surgical in origin, the liver usually recovers significant function to be able to sustain life within a couple of weeks, except for cases of fulminant hepatic failure (FHF), where hepatic regeneration is neither rapid nor sufficient enough to keep the individual alive, and end-stage cirrhosis, where hepatic regeneration cannot occur. Takahashi, T., et al., "Artificial liver state of the art", in Digestive Diseases and sciences, Vol. 36, No. 9 (September 1991). Pg. 1327-1340.
For these reasons the desirability of an artificial liver is well appreciated in the art. (JAUREGUI, H. O., et al., "Hybrid Artificial Liver", in Szycher, N. (Ed.), Biocompatible Polymers, Metals, and Other Composites (Lancaster, Pa., Technomic Pub.) 1983, Pg. 907-928; Matsumura U.S. Pat. No. 3,734,851.
Several devices which perform the function of the liver have been proposed. Haggar, et al., "Neonatal Hepatocyte Culture on Artificial Capillaries. A Model for Drug Metabolism and the Artificial Liver", ASAIO J. 6:26-35 (January/March 1983), Jauregui, H. O., et al., "Adult Rat Hepatocyte Cultures as the Cellular Component of an Artificial Hybrid Liver", and Paul, J. (Ed.), Biomaterials in Artificial Organs, (MacMillan) 1983, Pg. 130-140, describes experiments in which hepatocyte (healthy liver cells) were grown on external surfaces of and into walls of hollow, semipermeable fibers in a cartridge. The later reference suggests treating the fibers with collagen prior to seeding with hepatocyte to improve attachment. U.S. Pat. No. 5,043,260 to Jauregu discloses a perfusion device to grow and maintain hepatocyte. It includes a porous membrane to separate a perfusion compartment from a hepatocyte compartment and employs oligosaccharide lectin recognition linkage to attach hepatocyte to a biopolymer support member in the hepatocyte compartment. Demetriou, et al., "New Method of Hepatocyte Transplantation and Extracorporeal Liver Support" Ann, Surg., Sep. pg. 259-271;1986 shows a technique that allows hepatocyte attachment on collagen coated microcarriers which is placed in a chromatography column which is then perfused.
EP Application 9040158 discloses using a cell-culturing substrate to cause adhesion between the hepatocytes and a synthetic high molecular membrane layer. Lie, et al., "Successful Treatment at Hepatocyte Coma by a New Artificial Liver Device in the Pig" Res. Exp. Med (1985) 185, 483-492 teaches using liver pieces or cubes held by a porous membrane in a perfusion chamber.
Wolf, F. W., and Munkelt, B. E., "Bilirubin Conjugation by an Artificial Liver Composed of Cultured Cells and a Synthetic Capillaries," Vol. 21 Trans. Amer. Soc. Artif. Int. Organs, 1975, Pg. 16-23, describes experiments in which rat hepatoma (tumorous liver) cells were provided in the regions between hollow semipermeable fibers and a cartridge and blood was passed through these fibers and treated by the hepatoma cells. In such hollow fiber devices, the fibers are used to isolate these cells from the patient's immune defense system and have pore sizes so as to permit transfer of toxic substances. Cai, Z., et al., "Microencapsulate Hepatocyte for Bio-Artificial Liver Support" Artif. Organs, 12:388-393,1988 teaches encapsulating hepatocytes within alginate-polylysine membranes and serve as a liver support system.